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Flavaglines alleviate doxorubicin cardiotoxicity: implication of Hsp27.

ABSTRACT:

Background

Despite its effectiveness in the treatment of various cancers, the use of doxorubicin is limited by a potentially fatal cardiomyopathy. Prevention of this cardiotoxicity remains a critical issue in clinical oncology. We hypothesized that flavaglines, a family of natural compounds that display potent neuroprotective effects, may also alleviate doxorubicin-induced cardiotoxicity.

Methodology/principal findings

Our in vitro data established that a pretreatment with flavaglines significantly increased viability of doxorubicin-injured H9c2 cardiomyocytes as demonstrated by annexin V, TUNEL and active caspase-3 assays. We demonstrated also that phosphorylation of the small heat shock protein Hsp27 is involved in the mechanism by which flavaglines display their cardioprotective effect. Furthermore, knocking-down Hsp27 in H9c2 cardiomyocytes completely reversed this cardioprotection. Administration of our lead compound (FL3) to mice attenuated cardiomyocyte apoptosis and cardiac fibrosis, as reflected by a 50% decrease of mortality.

Conclusions/significance

These results suggest a prophylactic potential of flavaglines to prevent doxorubicin-induced cardiac toxicity.

SUBMITTER: Bernard Y

PROVIDER: S-EPMC3204970 | biostudies-literature |

REPOSITORIES: biostudies-literature

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